The objective of the proposed research is to quantitatively characterize the individual sensitivities and the interaction of exogenous sympathetic (norepinephrine) and parasympathetic (acetylcholrine) neurotransmitters on glucose stimulated insulin secretion from beta cells obtained from normal and genetically diabetic (DB/DB) mice and sham and VMH lesioned obese rats under specific, reproducible in vitro experimental conditions. The sensitivity of glucose induced insulin secretion to exogenous norepinephrine or acetylcholine will be determined by estimating insulin secretion from perifused pancreatic or isolated pancreatic islets exposed to six concentrations of neurotransmitter at glucose concentrations of 5, 10 and 20 mM. The interaction of norepinephrine and acetylcholine will be characterized by experimentally estimating the rates of glucose induced secretion from pancreatic tissue simultaneously exposed to selected concentrations of both norepinephrine and acetylcholine. These estimates will be compared with those obtained when pancreatic tissue is exposed to the same concentrations of each neurotransmitter alone or neither neurotransmitter. These studies will provide a description of the dynamics of glucose induced insulin secretion and the effects of physiological concentrations of norepinephrine and/or acetylcholine on those dynamics. Dose-response relationships of beta cells and the effects of the neurotransmitters on those relationships will also be determine. The interaction among norepinephrine and acetylcholine will also be determined in beta cells from genetically diabetic mice and VMH lesioned obese rats. These results will be compared to the results obtained with beta cells from normal mice and rats, to test the hypothesis that pancreatic adaptation to the spontaneous diabetic state or/and an experimentally induced obese state occurs, at least in part, by an alteration of post-synaptic sensitivity to one or both neurotransmitters.